Compositions for reducing elution of therapeutic agents from teeth

ABSTRACT

A dentrifice composition containing a water-dispersible, membrane-forming material which, when applied to tooth surfaces in an oral environment, attaches thereto and forms a substantially continuous, hydrophobic barrier thereon which substantially reduces elution of a previously applied therapeutic agent.

CROSS REFERENCE TO RELATED APPLICATION

.[.This is.]. .Iadd.This is a reissue of application Ser. No. 176,680filed Aug. 11, 1980, now U.S. Pat. No. 4,304,766, which was .Iaddend.adivision of application Ser. No. 26,402 filed Apr. 2, 1979, now U.S.Pat. No. 4,243,658, which was a continuation-in-part of Ser. No. 865,681filed Dec. 29, 1977, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compositions for topical application to teeth.More particularly it relates to compositions and methods whichsubstantially reduce the elution of a previously applied therapeuticagent from teeth. The compositions and methods of the invention areespecially useful in inhibiting the growth of cariogenic bacteria andpreventing the formation of plaque on teeth in an oral environment.

Dental plaque results when cariogenic bacteria (e.g., Streptococcusmutans) collect in colonies and form deposits on tooth surfaces. Thepresence of the bacteria and deposits is extremely detrimental to thehealth of the tooth for, if left unchecked, they may result in infectedgingival tissue, the formation of dental caries and possibly periodontaldisease. In extreme cases their presence may even result in the loss ofteeth. Many attempts have been made to control or prevent both theoccurrence of dental caries and the formation of dental plaque. Forexample, fluoride solutions or gels have been used. Treatment with thesematerials is typically performed in a dental office at periodic, but notfrequent, intervals. Such treatments are primarily intended to rendertooth enamel more resistant to the acid action caused by plaque. They donot, however, result in plaque control for an extended period sinceplaque reestablishes itself on the teeth shortly after ingestion offood.

Even when the frequency of application of such solutions and gels isincreased only partial control has been shown. For example, studieswherein a fluoride-containing solution (1% fluoride concentration) wasapplied four to five times in the course of a year have demonstratedthat this technique had only limited success due to the rapidreestablishment of plaque in the oral cavity. Moreover, the dailyapplication of a fluoride gel by means of a custom-fitted polyvinylmouthpiece for a period of twenty-one months also showed no substantialchange in plaque formation among treated and untreated patients. See"Clinical Anticaries Effect of A Repeated Sodium Fluoride Application byMouthpiece," Journal of the American Dental Association, V. 75, No. 3,September, 1967, pages 638-644.

As a result, there has been no truly effective prophylactic treatmentfor teeth made available. However, the present invention provides such atreatment.

SUMMARY OF THE INVENTION

In accordance with the present invention there is provided a dentrificecomposition for substantially reducing elution of a previously appliedtherapeutic agent from teeth, said composition comprising:

at least one ingredient selected from the group consisting oftherapeutic agents, polishing agents, surfactants, flavoring agents,sweetening agents, thickening agents and humectants, and at least about0.05% by weight, and preferably from about 0.1 to 5% by weight, of awater-dispersible, membrane-forming material which, when applied to thesurface of teeth in an oral environment, forms a substantiallycontinuous hydrophobic barrier thereon which substantially reduces theelution of said previously applied therapeutic agent from said tooth.

In another embodiment of the present invention there is provided amethod for inhibiting plaque formation on teeth which comprisescontacting the teeth with an effective amount of the above-describedcomposition.

As they are used herein, the following terms have the followingmeanings:

Dentifice Compositions

Compositions for topical application to the teeth such as mouthwashes orrinses, toothpastes, gels, etc.

Water Dispersible Materials

Materials which may be either dispersed or dissolved in aqueous media ata level at least about 10 parts of such material per one million partsof media (i.e., 0.001%), and preferably at a level of at least about 100parts of such material per one million parts of media (i.e., 0.01%).

Hydrophobic Barrier

A layer which does not adsorb or absorb water.

The present invention provides a simple and effective composition andprocess by which cariogenic bacteria and plaque formation may becontrolled. The barrier formed by compositions of the inventionsubstantially reduces the elution of a previously applied therapeuticagent (i.e., dental fluoride treatments), thereby prolonging theeffectiveness of such agents. Moreover, compositions of the inventionneed be applied only periodically (e.g., once daily) in order to achievethe desired reduction in elution and resultant control of caries andplaque.

DETAILED DESCRIPTION OF THE INVENTION

A variety of membrane-forming materials are useful in the presentinvention. They include polymeric and nonpolymeric, ionic and nonionicmaterials. Ionic materials are those which when provided in aqueoussolution, are attracted to either the positive or negative electrodeduring electrolysis. Thus, anionic materials are attracted to thepositive electrode and cationic materials are attracted to the negativeelectrode. Nonionic materials are those materials which, when providedin aqueous solution, are not normally attracted to either the positiveor negative electrode during electrolysis.

Anionic Membrane-Forming Materials

Anionic membrane-forming materials useful in the present invention arebelieved to attach to tooth surfaces and form a substantially continuousbarrier thereon by complexing with calcium present in the teeth. Thestrength of the complex structure formed may be represented by theformation constant of the complexing agent. This constant is expressedin terms of log₁₀ K and is based upon the complex formed between themembrane-forming material and a ligand on the tooth surface. Theformation constant is measured at about 25° C. and an ionic strengthapproaching 0 from the following equation: ##EQU1## In these formulae Wrepresents the membrane-forming material, L represents the ligand whichcomplexes with W and WL represents the complex formed between W and L.The bracketed symbols indicate the concentration of the indicatedmaterial at equilibrium.

The formation constant of useful anionic membrane-forming materials isin the range of about 0.5 to 8. Preferably, it is in the range of about0.6 to 6. A formation constant greater than 8 indicates a very strongcalcium complexor. Such complexors tend to decalcify the tooth (i.e.,withdraw the calcium from the tooth), thereby weakening its resistanceto disease and wear.

Polymeric Anionic Membrane-Forming Materials

The polymeric anionic membrane-forming materials useful in the presentinvention comprise a class of polymers having a polyolefinic main chainwith acidic functionalities pendant therefrom. Typical of the materialswhich can comprise the polyolefinic main chain are polymers of ethylene,propylene, styrene, unsaturated carboxylic acids, (especially thosecontaining up to about 5 carbon atoms) and copolymers of two or more ofthese materials.

The acid functionalities pendant from the polyolefinic main chain areselected from

--COOM,

--PO(OM)₂

--OPO(OM)₂

--SO₃ M

--OSO₃ M

wherein M is selected from hydrogen, alkali metal (e.g., sodium,potassium, lithium, etc.), ammonium and amine groups.

Representative polymeric anionic membrane-forming materials useful inthe present invention are:

(a) Polyacrylic acid, having the repeating unit ##STR1## a molecularweight in the range of 2,000 to 4,000,000, available from the AldrichChemical Company;

(b) "Separan AP 30," having the repeating unit ##STR2## and a molecularweight of about 2,000,000, available from the Dow Chemical Company;

(c) Sodium polystyrenesulfonate, having the repeating unit ##STR3## anda molecular weight in the range of about 5,000 to 6,000,000, availablefrom the Dow Chemical Company;

(d) "Gantrez AN", having the repeating unit ##STR4## available from GAFCorporation;

(e) "EMA" polymers, having the repeating unit ##STR5## available fromthe Monsanto Chemical Company;

(f) Polyvinyl phosphate, having the repeating unit ##STR6## commerciallyavailable from Polysciences, Incorporated; and

(g) Copolymers of acrylates which contain pendant carboxyl groups, suchas the "Carboset" resins available from the B. F. Goodrich ChemicalCompany.

Nonpolymeric Anionic Membrane-Forming Materials

The nonpolymeric anionic membrane-forming materials useful in thepresent invention comprise a class of materials having a nonionicaliphatic portion and an anionic terminal group. They may be generallyrepresented by the formula R¹ Z wherein R¹ is the aliphatic portion ofthe compound and Z is the anionic terminal group.

The aliphatic portion may be saturated or unsaturated and it may bestraight or branched chain. Additionally, it may be a hydrocarbon orfluorocarbon radical. Moreover, the aliphatic portion may contain heteroatoms selected from oxygen, nitrogen and sulfur.

Z may be joined directly to R' or, alternatively, there may be adivalent linking group Q which joins R' and Z. Q must not interfere withthe formation of the complex structure between the anionic material andthe tooth surface.

The Z groups useful in the nonpolymeric membrane-forming materials areselected from

--COOM

--PO(OM)₂

═POOM

--OPO(OM)₂

--SO₂ OM

--OSO₂ OM

--PS(SM)₂

═PSSM

wherein M is as defined previously.

Representative of useful Q groups are hydrocarbon groups containing from1 to about 30 carbon atoms, oxygen, sulfur and --SO₂ O--. Thehydrocarbon groups may be straight chain or branched chain and mayinclude unsaturation and aromatic (e.g., cyclic) groups. Moreover, thehydrocarbon groups may contain heteroatoms in the skeletal chain.Typically the hetero atoms are selected from the group consisting ofoxygen, nitrogen and sulfur.

A number of nonpolymeric anionic materials are useful as themembrane-forming material. One group of such materials containssubstantial quantities of fluorine in the main chain. Thus, for example,the perfluoroalkanesulfonamidoalkyl esters of phosphorous acids havebeen found useful. These compounds have the formula

    [R.sub.f SO.sub.2 N(R.sup.2)R.sup.3 0].sub.m PX(XB).sub.3-m

wherein R_(f) is a monovalent, stable, inert, fluorinated, saturatedaliphatic nonpolar radical; R² is hydrogen, alkyl of from 1 to 6 carbonatoms, aryl, cycloalkyl, aralkyl or alkaryl; R³ is an alkylene, arylene,alkarylene or aralkylene bridging group containing from 1 to 12 carbonatoms, m is 1 or 2; X is oxygen or sulfur; and B is hydrogen, alkyl,aryl, cycloalkyl, alkaryl, or aralkyl (each of up to 20 carbon atoms)alkali metals (e.g., sodium, potassium, lithium, etc.), ammonium, oramine groups.

The R_(f) radical can be straight chain, branched chain or, ifsufficiently large, cyclic. Additionally, it can be a combination ofcyclic, branched and straight chain, (e.g., alkylcycloaliphatic). Theskeletal chain of the R_(f) radical can include catenary oxygen and/ortrivalent nitrogen hetero atoms bonded only to carbon atoms. Such heteroatoms provide stable linkages between fluorocarbon groups and do notinterfere with the inert character of the radical.

The R_(f) radical has from about 4 to 16 carbon atoms; preferably fromabout 6 to 12 carbon atoms; and most preferably 8 carbon atoms.Moreover, R_(f) generally contains from about 40 to 80 weight percent,and preferably from about 50 to 80 weight percent, fluorine.Correspondingly the fluorochemical material of formula I will containfrom about 4 to 70 weight percent fluorine.

The most preferred R_(f) radicals are fully or substantially fullyfluorinated. Thus they are perfluoroalkyl groups (e.g., C_(n) F_(2n+1)--). Additionally the terminal portion of the R_(f) group preferablycontains a --CF₃ group, and most preferably the terminal portion alsohas at least three fully fluorinated carbon atoms, (e.g., CF₃ CF₂ CF₂--).

R² may be hydrogen or a straight or branched chain alkyl, aryl,cycloalkyl, alkaryl or aralkyl group. Preferably it is a straight chainalkyl group containing 2-3 carbon atoms.

R³ is a divalent bridging group. It may be straight chain or branchedchain and preferably is an alkylene group that contains from 2 to 8carbon atoms.

Representative examples of useful perfluoroalkanesulfonamidoalkyl estersof phosphorous acids useful in the present invention include

    [C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 0].sub.2 PSSH

    [C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 0].sub.2 POOH

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH).sub.2

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.10 H.sub.20 OPO(OH).sub.2

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OP(OH)(O)OC.sub.18 H.sub.37

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.4 H.sub.9)C.sub.2 H.sub.4 OPO(OH).sub.2

The preparation of these compounds is described in U.S. Pat. No.3,094,547 (for those wherein X is oxygen). Thus the appropriateperfluoroalkyl alcohol may be reacted with phosphorous oxytrichlorideabove 50° C. to produce the corresponding dichloride. The dichloridemay, in turn, be hydrolyzed to produce the phosphate.

The preparation of these compounds when X is sulfur is also known andmay be carried out by reacting the appropriate perfluoroalkyl alcoholwith phosphorous pentasulfide followed by refluxing in a non-reactivesolvent such as benzene or isopropyl ether. Additional details on thepreparation of dithiophosphate esters may be found in InorganicSynthesis, Vol. 6, p. 142 (McGraw-Hill, 1960).

Yet other nonpolymeric anionic fluorochemicals useful as themembrane-forming material are the fluoroalkanephosphates which may berepresented by the formula

    [C.sub.8 F.sub.2g+1 CH.sub.2 O].sub.k PO(OM).sub.q         (II)

wherein M is selected from hydrogen, alkali metal (e.g., sodium,potassium, lithium), ammonium and amine groups, and g is an integer offrom 1 to 10, k is 1 or 2 and q is 3-k. These materials are commerciallyavailable from E. I. Du Pont de Nemours as "Zonyl FSP."

Another class of nonpolymeric anionic materials useful in the presentinvention is the perfluoroalkanesulfonamidoalkyl carboxylic acids of theformula

    R.sub.f SO.sub.2 N(R.sup.2)R.sup.3 COOM                    (III)

wherein R_(f), R² and R³ are as defined in formula I and M is as definedin formula II. The preparation of these compounds is described in U.S.Pat. No. 2,809,990. Thus the appropriate perfluoroalkanesulfonamide maybe converted to a sulfonamide salt which may then be converted to anester of the desired acid which may in turn be hydrolyzed to the acid orthe salt.

Representative examples of perfluoroalkanesulfonamidoalkyl carboxylicacids useful in the present invention include

    C.sub.8 F.sub.17 SO.sub.2 N(CH.sub.3)(CH.sub.2).sub.10 COOH

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)CH.sub.2 COOH ##STR7##

Yet another class of the nonpolymeric anionic fluorochemicals useful asthe membrane-forming material are the fluorocarbon monocarboxylic acidsof the formula

    R.sub.f COOM                                               (IV)

wherein R_(f) is as defined in formula I and M is as defined in formulaII. The preparation of these compounds is described in U.S. Pat. No.2,567,011.

Representative examples of fluorocarbon monocarboxylic acids useful inthe present invention include

C₈ F₁₇ COOH

C₁₁ F₂₃ COOH

Still another class of nonpolymeric anionic fluorochemicals useful asthe membrane-forming material are represented by the formula

    R.sub.f R.sup.3 COOM                                       (V)

wherein R_(f) and R³ are as defined in formula I and M is as defined informula II. These compounds are described in U.S. Pat. No. 2,951,051.

Representative examples of compounds of formula V include

    C.sub.8 F.sub.17 CH.sub.2 CHClC.sub.8 H.sub.16 COOH

    C.sub.8 F.sub.17 C.sub.10 H.sub.20 COOH

Yet another class of nonpolymeric anionic fluorochemicals useful in thepresent invention are the perfluoroalkanesulfonate esters of the formula

    R.sub.f SO.sub.2 OY                                        (VI)

wherein R_(f) is as defined in formula I and Y is an aryl group. Thepreparation of these compounds is described in U.S. Pat. No. 3,346,612.Thus, these compounds may be prepared by reacting an appropriatephenolic compound with an appropriate perfluoroalkanesulfonyl fluoride.

Representative of useful perfluoroalkanesulfonate esters are ##STR8##

Still another class of nonpolymeric anionic fluorochemicals useful inthe present invention are the fluorocarbon sulfonic acids and theirderivatives. These compounds have the formula

    R.sub.f SO.sub.2 OM                                        (VII)

wherein R_(f) is as defined in formula I and M is as defined in formulaII. The preparation of these compounds is described in U.S. Pat. No.2,732,398. A particularly useful compound of this type is C₈ F₁₇ SO₂ OK.

Nonfluorinated materials are also useful as nonpolymeric anionicmaterials in the present invention. One class of such materials is thecarboxylic acids of the formula

    R.sup.5 COOM                                               (VIII)

wherein R⁵ is a hydrocarbon group, preferably alkyl, containing from 6to 24 carbon atoms and M is as defined in formula II. The R⁵ group maybe straight or branched chain and may contain unsaturation. Preferably,however, the carboxylic acids are saturated. When the compositionsemploying materials of formula VIII as the membrane-forming material areformulated in water, the acid should be provided in its water-solublesalt form.

Representative examples of useful carboxylic acids of formula VIIIinclude lauric, myristic, palmitic, stearic and oleic acids.

Another class of nonfluorinated material useful as the membrane-formingmaterial comprises the organic phosphates, of the formula

    [R.sup.6 O].sub.m PO(OM).sub.3-m                           (IX)

wherein R⁶ is a hydrocarbon group containing from about 10 to 20 carbonatoms, M is as defined in formula II and m is 1 or 2. Representativeexamples of useful organic phosphates of formula IX include (C₁₆ H₃₃ O)₂POOH and (C₁₈ H₃₇ O)₂ POOH.

Still other anionic non-polymeric materials may be used as themembrane-forming material. Thus, aliphatic sulfonates of the formula

    R.sup.6 SO.sub.2 OM                                        (X)

wherein R⁶ is as defined in formula IX and M is as defined in formula IIare also useful. Representative examples of useful aliphatic sulfonatesinclude C₁₂ H₂₅ SO₂ ONa and sodium dioctyl sulfosuccinate, i.e.,##STR9## Sodium dioctyl sulfosuccinate is commercially available as"Aerosol OT" from American Cyanamide Company.

Another useful class of nonpolymeric, anionic, membrane-formingmaterials is the N-acyl alkylaminoalkanoic acids of the formula

    R.sup.6 CON(R.sup.2)R.sup.3 COOM                           (XI)

wherein R⁶ is as defined in formula IX, R² and R³ are as defined informula I and M is as defined in formula II. A particularly usefulalkylaminoalkanoic acid is C₁₁ H₂₃ CON(CH₃)CH₂ COONa.

Yet another useful class of nonpolymeric, anionic, membrane-formingmaterials is the hydroxamic acids of the formula

    R.sup.6 CONHOH                                             (XII)

wherein R⁶ is as defined in formula IX. Particularly useful hydroxamicacids are the fatty acid hydroxamic acids.

Amine salts of fatty acids have also been found useful as themembrane-forming material. These compounds are known and may be preparedby reacting an amine (e.g., triethanol amine) with a fatty acid (e.g.,stearic acid). One particularly useful compound of this type is thetriethanol amine salt of stearic acid.

Cationic Membrane-Forming Materials

Cationic membrane-forming materials useful in the present invention arebelieved to attach to tooth surfaces via a complexing interactionbetween the cationic portion of the material and the proteinaceousportion of the tooth. A variety of cationic materials may be used as themembrane-forming material. They include polymeric and nonpolymericmaterials.

Polymeric Cationic Membrane-Forming Materials

The polymeric cationic membrane-forming materials useful in theinvention comprise a class of polymers containing nitrogen in theirbackbone. They may have molecular weights as low as about 100 or higherthan about 100,000.

Representative polymeric cationic membrane-forming materials are:

(a) Polydimeryl polyamine, a polydimeryl polyamide which has a molecularweight of about 8000, and an amine number of about 120 and iscommercially available from General Mills Chemical Co;

(b) Polyethylene imine which has the repeating unit --CH₂ -CH₂ NH--_(n),and a molecular weight of about 100,000 and is commercially availablefrom Dow Chemical Co.;

(c) 1,5-dimethyl diazaundecamethylene polymethobromine hexadimethrinebromide, a quaternary composition which has the repeating unit ##STR10##and is commercially available from Aldrich Chemical Company asPolybrene;

(d) Poly(N,N-dimethyl-3,5-dimethylenepiperidinium chloride) which hasthe repeating unit ##STR11## and is commercially available from AldrichChemical Company; and

(e) "Protamine" a grouping of simple proteins which yield only aminoacids, especially diamino acids, upon cleavage by enzymes or acids andis commercially available from Pflatz and Bauer, Inc.

Nonpolymeric Cationic Membrane-Forming Materials

The nonpolymeric cationic membrane-forming materials useful in thepresent invention comprise a class of materials having a non-ionicaliphatic portion and a cationic terminal group. They may be generallyrepresented by the formula R¹ D wherein R¹ is the aliphatic portion ofthe compound and is as defined previously and D is the cationic terminalgroup.

D may be joined directly to R¹ or, alternatively, there may be adivalent linking group Q which joins R¹ and D. Q must not interfere withthe formation of the complex structure between the cationic material andthe two surfaces and is as defined previously herein.

Representative examples of cationic terminal groups (D) useful in thepresent invention include

    --NHC.sub.2 H.sub.4 NHC.sub.2 H.sub.4 NH.sub.2

    --NH.sub.2

    --NHC.sub.2 H.sub.4 NH.sub.2 ##STR12##

    N(CH.sub.3).sub.2 C.sub.2 H.sub.4 OH.H.sub.2 PO.sub.4.sup.⊖

    --N(CH.sub.3).sub.3.Cl.sup.⊖

A number of nonpolymeric cationic materials are useful as themembrane-forming material. One group of useful materials containssubstantial quantities of fluorine in the main chain. Thus, for example,the distally perfluoroalkanesulfonamido amines described in U.S. Pat.No. 3,458,571 have been found useful. These compounds have the formula

    R.sub.f SO.sub.2 N(R.sup.2)R.sup.3 NHA                     (XIII)

wherein R_(f), R² and R³ are as described in formula I and A is a proton(e.g., hydrogen) or a poly(alkylamino) group.

Representative examples of compounds according to formula XIII include

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 NHC.sub.2 H.sub.4 NH.sub.2

    C.sub.8 F.sub.17 SO.sub.2 NHC.sub.2 H.sub.4 NH.sub.2 ##STR13##

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 NHC.sub.2 H.sub.4 NH.sub.2

Another class of nonpolymeric cationic fluorinated materials useful inthe present invention are the quaternary derivatives of theperfluoroalkanesulfonamidopolymethylenedialkylamine compounds. Thesederivatives are described in U.S. Pat. No. 2,759,019. They may berepresented by the formula

    R.sub.f SO.sub.2 N(R.sup.2)R.sup.3 N.sup.+ R.sub.3.sup.7 E.sup.-(XIV)

wherein R_(f), R², and R³ are as described in formula I, R⁷ is an alkylgroup containing from 1 to 6 carbon atoms and E is an anion. Typicalanions include H₂ PO₄.sup.⊖, NO₃.sup.⊖ and halogens such as iodide,bromide, and chloride.

Representative examples ofperfluoroalkanesulfonamidopolymethylenedialkylamine quaternary derivatesinclude

    C.sub.8 F.sub.17 SO.sub.2 N(CH.sub.3)C.sub.2 H.sub.4 N.sup.30 (CH.sub.3).sub.3.Cl.sup.-

    C.sub.8 F.sub.17 SO.sub.2 NHC.sub.3 H.sub.6 N.sup.+ (CH.sub.3).sub.3.Cl.sup.-

C₈ F₁₇ SO₂ NHC₃ H₆ N⁺ (CH₃)₂ C₂ H₄ OH.H₂ PO₄ ⁻

Nonfluorinated materials are also useful as nonpolymeric cationicmembrane-forming materials in the present invention. Thus, for example,alkyl amines of the formula C_(n) H_(2n+1) NH₂, wherein n is from 4 to20, have been found useful.

Alkyl guanidines have also been found useful as membrane-formingmaterials of the present invention. For example, C₁₆ H₃₃ NHC(NH)NH₂.HClhas been found useful as a membrane-forming material.

Nonionic Membrane-Forming Materials

Useful nonionic membrane-forming materials are believed to attach totooth surfaces by interacting with either or both of (i) the hydroxylgroups of the hydroxyapetite (i.e., C₁₀ (PO₄)₆ (OH)₂) or (ii) thehydroxyl groups present on the tooth surfaces from water or saliva inthe mouth. In any event, useful nonionic membrane-forming materials maybe represented by the formulae

    [R.sup.8 ].sub.b -Si-[R.sup.9 ].sub.4-b                    (XV)

    [R.sup.10 ].sub.x -Ti-[OR.sup.11 ].sub.4-x                 (XVI)

    [R.sup.12 ].sub.x Ti[R.sup.11 ].sub.4-x                    (XVII)

In these formulae R⁸ is selected from hydrocarbon and fluorocarbongroups or combinations of hydrocarbon and fluorocarbon groups which maycontain up to 25 carbon atoms. When R⁸ contains fluorocarbon terminalgroups it is preferred that they be separated from the Si atom by analkylene group. R⁸ may be aliphatic, aromatic or a combination ofaliphatic and aromatic groups which may contain heteroatoms selectedfrom nitrogen, sulfur, oxygen and silicone. Preferably no two of saidhetero atoms are adjacent, and the oxygen atoms present are in the formof ether linkages. R⁹ is an alkoxy group containing from 1 to 6, andpreferably from 1 to 3, carbon atoms. R¹⁰ is selected from hydrocarbongroups, preferably alkoxy groups, containing from 1 to 20 carbon atomsand preferably from 1 to 10 carbon atoms. R¹¹ is selected fromhydrocarbon groups of 1 to 20 carbon atoms which may be aliphatic,aromatic or aliphatic and aromatic and which may contain nitrogen,phosphorous, oxygen and sulfur substitution. R¹² is a heterocyclic groupcontaining carbon oxygen and hydrogen. The value of b and x is 0, 1, 2or 3.

One class of materials according to formulae XV and XVI useful in thepresent invention include fluorocarbon siloxanes of the type describedin U.S. Pat. No. 3,442,664 and having the formula

    R.sub.f R.sup.13 Si(OR.sup.14).sub.3                       (XVIII)

wherein R_(f) is as defined in formula I, R¹³ is an alkylene group offrom 2 to 4 carbon atoms and R¹⁴ is an alkyl group of from 1 to 4 carbonatoms.

Representative examples of useful fluorocarbon siloxanes according toformula XVIII include

    C.sub.8 F.sub.17 CH.sub.2 CHClSi(OCH.sub.3).sub.3

    C.sub.8 F.sub.17 CH.sub.2 CHClSi(OC.sub.2 H.sub.5).sub.3

Other fluorocarbon siloxanes useful as the membrane-forming material inthe present invention include: ##STR14##

    C.sub.7 F.sub.15 CONHC.sub.3 H.sub.6 Si(OC.sub.2 H.sub.5).sub.3

    (H.sub.5 C.sub.2 O).sub.3 SiC.sub.3 H.sub.6 NHCO(CF.sub.2 O).sub.x (CF.sub.2 CF.sub.2 O).sub.y CFCONHC.sub.3 H.sub.6 Si(OC.sub.2 H.sub.5).sub.3

    C.sub.18 H.sub.37 N(CH.sub.3).sub.2 C.sub.3 H.sub.6 Si (OCH.sub.3).sub.3 Cl.sup.-

This last compound is commercially available from Dow CorningCorporation as Q9-5700.

Compounds according to formulae XVI and XVII useful in the inventioninclude the organotitanates. Examples of these compounds include##STR15## The foregoing titanium compounds are available from KenrichPetro-chemicals as the Ken-react titanates.

Other ingredients may be added to the compositions of the presentinvention. For example, therapeutic agents, such as caries prophylacticagents, polishing agents, surfactants, flavoring and sweetening agents,thickening agents and humectants may be included using techniques whichare known to the art.

When such other ingredients are employed with (i) the anionicmembrane-forming materials or (ii) the cationic membrane-formingmaterials which have a calcium complexing moiety D, the otheringredients must be substantially free of polyvalent metal atoms, (e.g.,calcium, magnesium, etc.). These atoms interact with these particulartypes of membrane-forming materials and prevent them from forming thebarrier. Thus while a minor amount of such atoms may be present, thetotal amount present must not prevent the membrane-forming material frominteracting with the teeth. Preferably these compositions are free ofpolyvalent metal atoms.

With these factors in mind, then, suitable therapeutic agents, such ascaries prophylactic agents, include sodium fluoride, stannous fluoride,potassium fluoride, hexylamine, hydrofluoride, myristylaminehydrofluoride, betaine fluoride, glycine potassium fluoride, etc. Aparticularly preferred fluoride is sodium fluoride.

When such other ingredients are employed with (i) the nonionicmembrane-forming materials or (ii) the cationic membrane-formingmaterials which are free from calcium complexing moieties, suchingredients need not be substantially free from polyvalent metal atoms.

The therapeutic agents, when employed, are typically present insufficient concentration so as to provide an available fluoride ionconcentration of up to about 2% by weight, and preferably in the rangeof about 0.5-2% by weight, of the dentifrice composition. Additionally,it is preferred that the weight ratio of therapeutic ingredient tomembrane-forming material be in the range of about 1:0.5 to 1:5 and mostpreferably in the range of about 1:0.5 to 1:1.

Suitable polishing agents include abrasive materials such as nonionicpolymers. Representative of such materials are water-imperviouscrosslinked thermosetting resins (e.g., the condensation product ofmelamine and urea with formaldehyde), powdered polymethylmethacrylateand powdered polyethylene. Preferably the polishing agent is not soabrasive so as to scratch or unduly abrade the tooth surface or thedentin. Rather it only cleans the tooth surface. The polishing agentsmay comprise up to 95% by weight of the dentifrice composition.

Surfactants useful in the present invention include, for example,nonionic surfactants which are known to the art. These materialstypically comprise up to about 5% by weight of the dentifricecomposition.

Flavoring and sweetening agents useful in the invention include, forexample, the oils of wintergreen, peppermint, spearmint, sassafras andanise. Additionally small amounts of sweetening agents such assaccharin, dextrose, levulose, etc., may also be added to thecompositions. The flavoring and sweetening agents may comprise up toabout 5% by weight of the dentifrice composition.

Gelling or thickening agents useful in the invention include, forexample, water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxy methyl hydroxy ethyl cellulose,natural gums such as gum karaya, gum arabic, and gum tragacanth; andcolloidal magnesium-aluminum silicate or finely divided silica. Suchthickening agents may comprise up to about 5% by weight of thedentifrice composition.

When provided in solution, dentifrices of the present inventiontypically comprise a solution of the membrane-forming material in wateror a mixture of water and an alcohol. Typically the alcohol is a loweralkanol (e.g., ethanol, propanol, etc.). These compositions areparticularly useful as mouthwashes or rinses.

The present invention is further illustrated in the following examples.

EXAMPLE 1

This example demonstrates that compositions of the invention formsubstantially continuous barriers that reduce the elution of apreviously applied fluoride treatment from the teeth.

Separate bovine central incisors were used in the tests. A flat surfacewas provided on each tooth by first polishing each with 240 grit siliconcarbide abrasive paper; and then with 400 grit silicon carbide abrasivepaper. The teeth were then given a 5 minute soak with a 2% by weightsolution of sodium fluoride (NaF) in deionized water. One-half of thenumber of the teeth were then given a 5 minute soak with a 1% by weightsolution of membrane-forming material (C₁₆ H₃₃ O)₂ -POOH, in deionizedwater. The remaining teeth were given no treatment with themembrane-forming composition. All of the teeth were then tested forinitial water contact angle, initial fluoride level, water contact angleafter a 26 hour water soak and fluoride content after a 26 hour watersoak.

The water contact angle was measured by placing a drop of water on theflat polished surface of the tooth using a Model 710 "Hamilton"microliter syringe. The drop was then photographed using a Polaroid^(R)camera which had a telescopic lens. The maximum perpendicular height (h)of the drop from the surface of the tooth to the top of the drop and themaximum length (l) of the drop in contact with the surface of the toothwere measured. These values were used to calculate the contact angle--byinserting them in the formula

    (tan θ/2)=2h/l.

As the water contact angle increases the water repellancy of thesurfaces increases. High water contact angles (e.g., at least about 70°)are characteristic of the anionic membrane-forming materials.

The fluoride content was measured with an electron microprobe Model 400available from Materials Analysis Co. This was a destructive test sothat duplicate sets of teeth were tested in order to determine theinitial fluoride content and the fluoride content after water soak. Theresults obtained are given in Table V.

                                      TABLE V                                     __________________________________________________________________________                   INITIAL         26 HOUR WATER SOAK                                            CONTACT                                                                              FLUORIDE CONTACT                                                                              FLUORIDE                                               ANGLE  ON TOOTH ANGLE  ON TOOTH                                TOOTH TREATMENT                                                                              (°)                                                                           (COUNTS/SEC)                                                                           (°)                                                                           (COUNTS/SEC)                            __________________________________________________________________________    A.                                                                              NaF          21     1.7      --     --                                      B.                                                                              NaF + (C.sub.16 H.sub.33 O).sub.2 POOH                                                     100.4  1.2      --     --                                        Composition                                                                 C.                                                                              NaF          34     --       35.4   0.5                                     D.                                                                              NaF + (C.sub.16 H.sub.33 O).sub.2 POOH                                                     89     --       66.2   0.9                                       Composition                                                                 __________________________________________________________________________

Comparison of treatments A and B shows the dramatic increase in watercontact angle caused by the addition of the membrane-forming material(C₁₆ H₃₃ O)₂ -POOH. Comparison of treatments C and D shows that, evenafter soaking the teeth for 26 hours in water, the membrane remains onthe surface and that it substantially reduces elution of the initialfluoride treatment.

EXAMPLE 2

Bovine teeth were prepared and treated with NaF as described inExample 1. Certain of the teeth were then soaked for 5 minutes withcompositions containing various membrane-forming materials. Each of theteeth were then soaked in separate 100 ml deionized water baths for 24hours. The teeth were removed from the baths and each bath was thenanalyzed for fluoride ion content using a fluoride ion electrode. Theresults of these tests are set forth in Table VI.

                  TABLE VI                                                        ______________________________________                                                                  FLUORIDE                                                                      CONTENT                                                                       IN WATER                                            TOOTH TREATMENT           (μg/ml)                                          ______________________________________                                        A   2% NaF                    1.04                                            B   2% NaF +                  0.55                                                0.5% C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4              OPO(OH).sub.2 +                                                               97.5% deionized water                                                     C   2% NaF                    0.72                                            D   2% NaF + 1% Polyacrylic Acid (CH.sub.2 CH) +                                                            0.21                                                97% deionized water COOH                                                  E   NaF +                     0.43                                                1% [C.sub.18 H.sub.37.sup.+N(CH.sub.3).sub.2 C.sub.3 H.sub.6 Si(OCH.su        b.3).sub.3 ]Cl.sup.-  +                                                       97% deionized water                                                       ______________________________________                                    

Comparison of treatments A and B (run simultaneously) graphicallyillustrates the decrease in elution of the NaF as a result of thepresence of the membrane-forming material. Comparison of treatments Dand E with treatment C (run simultaneously but at a different time thantests A and B) further graphically illustrate the decrease in elution ofthe NaF as a result of the presence of the membrane-forming material.

EXAMPLE 3

This example demonstrates the durability of the membrane. Bovine centralincisors were prepared and the initial water contact angle measured asdescribed in Example 1. The teeth were then soaked for 5 minutes with0.1% by weight solutions of various membrane-forming materials indeionized water. The water contact angle was then measured after theteeth had been soaked in deionized water for 10 and 60 minutes and 24hours. The results are given in Table VII.

                  TABLE VII                                                       ______________________________________                                                           Water Contact Angle (°)                                                         10     60   24                                    Membrane-forming     ini-   min    min  hour                                  Material             tial   soak   soak soak                                  ______________________________________                                         ##STR16##           33.4    90    91    92.8                                   C.sub.8 F.sub.17 C.sub.10 H.sub.20 COOH                                                          38.5   114    102  110.4                                 C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH).sub.2                          34.2   101.5  93   50                                    ______________________________________                                    

The high water contact angles, even after 24 hours of water soaking,demonstrate that the membranes retain their integrity for extendedperiods of time.

EXAMPLE 4

The procedures of Example 3 were repeated except that the teeth weregiven a fluoride treatment before being soaked for 5 minutes with a 0.1%by weight solution of membrane-forming material in deionized water. Thefluoride treatment consisted of a 5 minute soak with an acidulatedphosphate fluoride which comprised 40 grams (g) of NaF, 11.8 ml of HF,126 ml of H₃ PO₄ and 1400 ml of deionized water. The results of thewater contact angle measurements are given in Table VIII.

                                      TABLE VIII                                  __________________________________________________________________________    MEMBRANE-FORMING WATER CONTACT ANGLE (°)                               MATERIAL         Initial*                                                                          4 Min                                                                             5 Hrs                                                                             24 Hrs                                                                            5 days                                       __________________________________________________________________________    C.sub.8 F.sub.17 SO.sub.2 H(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH).sub.2                      43.6                                                                              101.4                                                                             94  104 87.6                                         Triethanolamine salt of                                                                        38  102 78.4                                                                               80 -- stearic acid                              __________________________________________________________________________

This data demonstrates the durability of membranes formed formmembrane-forming materials according to the invention.

EXAMPLE 5

Bovine central incisors were sequentially polished with 120 grit, 400grit and 600 grit SiC abrasive papers so as to obtain a smooth, flat,uniform surface. The polished teeth were exposed to fluoride solution.One half of the number of the teeth were then used as controls while theremaining teeth were coated with various membrane-forming materials bydipping the teeth in an aqueous solution (0.5% by weight) for 5 minutesand then air-drying the treated teeth. All of the teeth were thenexposed to water by soaking them in two separate 5 microliter portionsof water for 15 minutes each. The fluoride remaining on the teeth aftersoaking was recovered by etching the teeth with a 5 microliter portionof 0.5 M perchloric acid which had been further diluted to 100microliters by volume. The amount of fluoride recovered was determinedby the hanging-drop fluoride electrode technique (P. Venkateswarlu,Analytical Chemistry: 46 878, 1974).

The amount of fluoride retained on the coated teeth and the controlteeth was then compared by dividing the amount retained on the coatedteeth by the amount retained on the control teeth.

The fluoride treatments, membrane-forming materials and results of thehanging drop test are set forth in Table IX.

                  TABLE IX                                                        ______________________________________                                                                       FLUO-                                                                         RIDE RE-                                                                      TENTION                                                                       (Ratio                                         FLUORIDE   MEMBRANE-FORMING    Coated:                                        TREATMENT  MATERIAL            Control)                                       ______________________________________                                        4% NaF, 5 min.                                                                           C.sub.8 F.sub.17 (CH.sub.2).sub.10 COOH                                                           2.3                                            4% NaF, 5 min.                                                                           Protamine Sulfate   18                                             4% NaF, 5 min.                                                                           (C.sub.16 H.sub.33 O).sub.2 POOH                                                                  1.7                                                                           1.4                                            4% NaF, 5 min.                                                                           (CH.sub.3).sub.2 CHOTi[OCOC.sub.16 H.sub.32 CH.sub.3 ].sub.3                                      1.8                                            5% SnF.sub.2, 5 min.                                                                     (CH.sub.3).sub.2 CHOTi[OCOC.sub.16 H.sub.32 CH.sub.3 ].sub.3                                      1.2                                                                           2.6                                                                           2.3                                                                           2.8                                                                           3.0                                            ______________________________________                                    

As can be seen from the data, the compositions of the inventionsubstantially reduce the elution of a previously applied fluoride.

EXAMPLE 6

Example 5 was repeated except a different water washing technique wasemployed. In this example the water washing comprised drip washing theteeth with water for a period of time and followed by etching the teethto recover the retained fluoride. Two etchings with the perchloric acidwere performed. The first gave a measure of the fluoride retained by thecoated teeth while the second gate a measure of the depth of fluoridetreatment.

The fluoride treatments, membrane-forming materials and results of thehanging drop test are set forth in Table X.

                                      TABLE X                                     __________________________________________________________________________    FLUORIDE  MEMBRANE-FORMING                                                                              WASHING                                             TREATMENT MATERIAL        TIME(HRS)                                                                            L.sup.1                                                                         L.sup.2                                    __________________________________________________________________________    4% NaF, 5 min.                                                                          C.sub.8 F.sub.17 (CH.sub.2).sub.10 COOH                                                       36     2.2                                                                             1.7                                                                         9.7                                                                             1.3                                        4% NaF, 5 min.                                                                          (C.sub.16 H.sub.33 O).sub.2 POOH                                                              36     2.5                                                                             1.6                                                                         1.2                                                                             1.3                                        4% NaF, 5 min.                                                                          (C.sub.3 H).sub.2 CHOTi[OCOC.sub.16 H.sub.32 CH.sub.3 ].sub.3                                 36     7.5                                                                             1.5                                                                         1.9                                                                             1.4                                        4% NaF, 5 min.                                                                          C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)CH.sub.2 COOK                                     36     1.4                                                                             1.0                                        Na.sub.2 PO.sub.3 F (0.1% F)                                                            C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)CH.sub.2 COOK                                     44     1.7                                                                             1.0                                                                         2.3                                                                             1.3                                                                         1.7                                                                             1.7                                        SnF.sub.2 (0.1% F)                                                                      C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)CH.sub.2 COOK                                     60     1.8                                                                             1.4                                        3 min.                           1.4                                                                             1.3                                        __________________________________________________________________________     L.sup.1 = first etching                                                       L.sup.2 = second etching                                                 

As can be seen from the data, treated teeth are resistant to elution ofa previously applied fluoride treatment.

What is claimed is:
 1. A dentifrice composition for substantiallyeffectively coating previously fluoride-treated teeth and therebyreducing elution of said fluoride from said teeth, said compositioncomprisinga fluoride-containing caries prophylactic agent provided thatsaid agent is substantially free from polyvalent metal atoms; and atleast about 0.05% by weight of an anionic water-dispersiblemembrane-forming material which, when applied to the surface of saidpreviously fluoride-treated teeth in an oral environment, complexes withthe calcium of said teeth and forms a substantially continuoushydrophobic barrier thereon which substantially reduces the elution ofsaid previously applied fluoride from said teeth and which, when atequilibrium with the complex, has a formation constant in the range ofabout 0.5 to 8, said anionic membrane-forming material being anon-polymeric fluorinated material selected from the group

    (R.sub.f SO.sub.2 N(R.sup.2)R.sup.3 O).sub.m PX(XB).sub.3-m

    (C.sub.g F.sub.2g+1 CH.sub.2 O).sub.k PO(OM).sub.q

    R.sub.f COOM

    R.sub.f R.sup.3 COOM

    R.sub.f SO.sub.2 OM

    .Iadd.R.sub.f SO.sub.2 OY .Iaddend.

wherein R_(f) is a monovalent, stable, inert, fluorinated, saturatedaliphatic non-polar radical containing from about 4 to 16 carbon atoms;R² is selected from hydrogen and alkyl groups containing from about 2 to3 carbon atoms; R³ is selected from alkylene, chloro- substitutedalkylene and alkarylene groups that contain from about 1 to 10 carbonatoms; X is selected from oxygen and sulfur; B is selected fromhydrogen, alkali metal, ammonium and amine groups, and alkyl, aryl,cycloalkyl, alkaryl, and aralkyl groups each containing up to 20 carbonatoms; M is selected from hydrogen, alkali metal, ammonium and aminegroups; .Iadd.Y is an aryl group; .Iaddend.m is 1 or 2; g is an integerof from 1 to 10; k is 1 or 2; and q is 3-k.
 2. A dentifrice compositionaccording to claim 1 wherein said membrane-forming material has theformula (R_(f) SO₂ N(R²)R³ O)_(m) PX(XB)_(3-m).
 3. A dentifricecomposition according to claim 2 wherein R_(f) is a fully fluorinatedalkyl radical containing eight carbon atoms, R² is selected fromhydrogen, methyl and ethyl and butyl, and R³ is ethylene.
 4. Adentifrice composition according to claim 3 wherein saidmembrane-forming material is selected from

    (C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 O).sub.2 PSSH

    (C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 O).sub.2 POOH

    .[.C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH.sub.2).].

    .Iadd.C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH).sub.2 .Iaddend.

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.10 H.sub.20 OPO(OH).sub.2

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OP(OH)(O)OC.sub.18 H.sub.37

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.4 H.sub.9)C.sub.2 H.sub.4 OPO(OH).sub.2.


5. A dentifrice composition according to claim 4 wherein saidmembrane-forming material is

    C.sub.8 F.sub.17 SO.sub.2 N(C.sub.2 H.sub.5)C.sub.2 H.sub.4 OPO(OH).sub.2.


6. A dentifrice composition according to claim 1 wherein saidmembrane-forming material has the formula

    R.sub.f COOM.


7. A dentifrice composition according to claim 6 wherein saidmembrane-forming material is selected from

    C.sub.8 F.sub.17 COOH

    C.sub.11 F.sub.23 COOH.


8. A dentifrice composition according to claim 1 wherein saidmembrane-forming material has the formula

    R.sub.f R.sup.3 COOM.


9. A dentifrice composition according to claim 8 wherein saidmembrane-forming material is selected from

    C.sub.8 F.sub.17 CH.sub.2 CHCl.sub.8 H.sub.16 COOH

    C.sub.8 F.sub.17 C.sub.10 H.sub.20 COOH.


10. A dentifrice composition according to claim 9 wherein saidmembrane-forming material is

    C.sub.8 F.sub.17 C.sub.10 H.sub.20 COOH.


11. A dentifrice composition according to claim 1 wherein saidmembrane-forming material has the formula R_(f) SO₂ OM.
 12. A dentifricecomposition to claim 11 wherein said membrane-forming material is C₈ F₁₇SO₂ OK. .Iadd.13. A dentifrice composition according to claim 1 whereinsaid membrane-forming material has the formula R_(f) SO₂ OY. .Iaddend..Iadd.14. A dentifrice composition according to claim 13 wherein saidmembrane-forming material is selected from ##STR17##.Iaddend.